Standard Operating Procedure for Determining Shelf Life And Stability Testing Programme

Determining Shelf Life And Stability Testing Programme is the stability testing programmed for all pharmaceutical products manufactured at Company facility confirm the stability of the products and compatibility.

PURPOSE

1. To describe the stability testing programmed for all pharmaceutical products manufactured at Company facility.
2. To confirm the stability of the products and compatibility with its container, while stored in accordance with labeling conditions and time, and with respect to product degradation. Pharmaceutical products will be tested at designated intervals for certain physical, chemical and microbiological properties.
3. To collect scientific evidence based on test results to determine the shelf life of products.

SCOPE

Applicable to all new, existing products involving significant change, trial batches, current marketed pharmaceutical preparations i.e. Eye drops, Solid dosage forms, Injectables, irrigation, dialysis, intravenous infusion & intravenous sets manufactured at Company facility.

DEFINITION

PD: Production

Stability: Continued conformity of the drug product to its specification.
Shelf life: Time interval that a drug product is expected to remain within the Approved expiry date specification, stored at labeled storage condition on the proposed container and closure.

PROCESS & RESPONSIBILITY

• Asst. QA manager/QA officer is responsible for preparing annual ongoing stability testing plan of current marketed products in consultation with PD department which is reviewed by QC manager and approved by QA manager.
• Stability protocol of product is prepared by asst. QA manager/ QA officer, reviewed by QA manager and finally approved by HOD QA/QC.
  QC manager is responsible for in time conduction of testing and reporting according to schedule.
• Testing frequency, storage conditions and the number of samples are based on climate zone the type and expiry of products.

Stability studies are conducted as follows:

• New products, never manufactured before at plant.
• Ongoing stability for current marketed products.
• Stability studies of existing products with significant changes like formula, material source, process, and packaging component change.
• Accelerated stability studies of trial batches.
• Test all products in accordance with their specifications.
• Frequency of testing and batch selection for current Marketed products (Ongoing stability)
• For stability testing one batch of the year for each product manufactured.
• In annual shelf life schedule only are included current marketed products. New products are not included in this schedule. New products are entered in this schedule only when the stability testing of first three batches have been completed.
• Annual shelf life schedule is circulated to QA department (ongoing stability testing schedule) so that extra quantity of sample can be taken during sampling.
• AM (QA) ensures that stability samples are placed in defined area.
• After batch selection AM (QA) shades the status block of ongoing stability studies plan respectively.
• Selected batch is entered in “ongoing stability studies” according to analysis frequency of current marketed products in shelf life. Each product is tested biannual on first year and then annually after one year of expiry.
• Product name, batch number, manufacturing date, expiry date and testing frequency is entered on the plan and is approved by HOD QA/QC.
• Scheduling of new products/Existing products involving critical & significant change.
• First three batches of a new product of each dosage form and of each significant different package type, selected for long term stability studies at labeled storage condition & at accelerated storage conditions (40±2oC & 75%±5%)
• Shelf life study plan of new products and stability protocol is prepared by asst. QA manager or QA officer when the first batch of that product comes in finish goods for analysis. Plan is finally approved by HOD QA/QC.
• Next batches of this product are entered on the same shelf life plan. Schedules and stability protocols of second and third batch have to be prepared when second & third batches are manufactured and come in finish goods ware house.
• In case of new product two types of schedules are prepared for stability study.
• Determining Shelf Life And Stability Testing Programme

1. Full design schedule
2. Reduced design schedule

• Full design schedule means that samples of every combination and of all design factors will test at all time. Testing frequency of new product is on quarterly basis for first year, then biannual for second year and then on annual basis after one year of expiry.
• Reduced design schedule is follow, if different strength or significant package types are launched at same time.
• Principles and considerations for reduced design;

1. Bracketing
2. Matrixing
3. Bracketing:

• Bracketing is that design of a stability schedule in which the samples on the extremes of certain design factors (e.g., strength, container size and / or fill) are tested at all time points (testing months) as in a full design.

Example:

In bracketing technique lowest and highest strength dosage forms are tested at every time point while omitting the middle one strength as shown below.

Key, B1 – B3 = indicates batch          T = sample tested

Bracketing (strength): Bracketing is applicable

• To strength of identical and closely related formulation.
• To strength were the relative amount of drug substance and excipients vary within the product size.
• Not applicable to different excipients among strength.

Example:
In bracketing technique lowest and highest strength dosage forms are tested at every time point while omitting the middle one strength as shown below.

Key, B1 – B3 = indicates batch          T = sample tested

Bracketing (container closure sizes, fills): Bracketing is

• Applicable to same container closure system where either the container size or fill varies while the other remains constant.
• Applicable with additional justification to same container closure system but both the container size and fill varies.
• Not applicable to different container closure system.
• Determining Shelf Life And Stability Testing Programme

Key, B1 – B3 = indicates batch          T = sample tested

Matrixing Determining Shelf Life And Stability Testing Programme

Matrixing is that design of a stability schedule in which a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested.
In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point.

Matrixing is Applicable to,

• Strength with identical and closely related formulation.
• Container size or fills of the same container closure system
• Different batches made with same equipment and process.

Applicable with additional justification:

• Where the relative amount of excipients change or different excipients are used.

Matrixing is Not applicable to,

• Different storage conditions
• Different test attributes

Matrixing considerations:

• Design should be balanced as far as possible so that each combination is tested to the same extent over the intended duration of the study and through the last time point prior to submission.
• Where time points are matrixed, all selected factor combinations are tested at the initial and final time points (and the last time point prior to submission).

Example:

T = sample tested

Determining Shelf Life And Stability Testing Programme

• After preparing schedule, sr. chemist enters selected batches in shelf life software of computer as a new product.
• New products are normally tested up to five years from their stated manufacturing date, to test the stability of product for a specified time period, but in case of any deviation from the shelf life specifications, shelf life study is terminated at that time period.

Stability study protocol

Protocol is prepared by the sr. chemist, reviewed by the QC manager, approved by QA manager and authorized by HOD (QA/QC).

• Product information
• Stability tests
• List of documents
• List of equipment’s
• Bracketing & matrixing techniques (if applicable)
• Testing schedule

1. Dosage form, type of stability (e.g. ongoing stability study) and storage conditions (e.g. 25±2oC/ 60±5% RH), purpose, responsibility are noted at the first page of protocol.
2. Product information (which includes composition, batch no., testing frequency, no. of units to be stored), list of all the relevant testing documents like analytical testing procedure of the product, product specification, stability review report and equipment’s to be used during stability study are listed.
3. Stability tests of relevant dosage form are mentioned on respective protocol.
4. Bracketing and matrixing techniques (if applicable) are planned on protocol.
5. Stability testing schedule which represents the no. of units removed during each time point of the stability study is mentioned at protocol.

Stability study testing and reporting:

• At the start of month sr. chemist reviews long term shelf life study plan and ongoing stability studies plan of the new and current marketed products and notes the batches whose testing is due in that month and informs about these batches to QC manager, who enters these in stability sample register.
• QC manger assigns sample to sr. chemist for testing.
• Shelf life samples are tested against specification of shelf life of products.
• Sr. chemist enters analysis results in stability sample register.
• Sr. chemist ensures that the product must be tested with the same validated analytical procedure as that was used at the time of initial testing.
• Product information and stability results after defined time interval are noted on by Asst. QC manager or sr. chemist and verified by QC manger.
• Any significant change (if occurs) is noted by Asst. QC manger or sr. chemist and verified by QC manager.
• Any change /deviation suggested during the whole study along with its reason is noted by asst. QC manager or sr. chemist and verified by QC manager & approved by QA manager.
• Brief description of any change, observations, deviation report conclusion whether or not the results meet specifications, location of relevant information and documents are noted on.
• Finally this report is reviewed by QA manager, approved by HOD.
• Determining Shelf Life And Stability Testing Programme
• The sr. chemist files shelf life report in the respective shelf life file, under the respective separator of that batch.
• After completion of testing and reporting, shelf life plan of products is revised as follows,
• from shelf life specifications, QC manager presents test results deviation report to HOD.

Deviation of results

Storage condition of shelf life sample

Determining Shelf Life And Stability Testing Programme

RECORD

• Shelf life stability review report
• Ongoing Stability review report.
• Stability sample register
• Stability testing programme
• Ongoing Stability testing programme
• Stability Study Protocol
• Climatic zone classification

REFERENCE Determining Shelf Life And Stability Testing Programme

1. Investigation of out of specification (OOS) results
2. ICH guideline for stability
3. DISTRIBUTION
4. HOD QA/QC
5. Manager – QA
6. SDM – QC
7. Sr. Chemist/ Chemist / Microbiologist and all concerned

AMENDMENT

1. A – First Issue
2. B – Amendments are made
3. C – Changes are made in clause
4. D- Updated as per Document Management System procedure
5. E – Clause are added to incorporate stability of products manufactured under third Party manufactured contract. Clause are added to provide records. Clause are revised to delete “ambient”. Amendments are also made in SOR. Clause updated.
6. F – Amendments are made some issues.
7. G– Revised to introduce bracketing, matrixing & protocol.
8. Determining Shelf Life And Stability Testing Programme